Long acting local anesthetic formulations hold great promise for the management of acute pain, as long lasting analgesia could be achieved with a single dose administered after surgery or trauma. Liposomal local anesthetic formulations have been shown to prolong analgesic duration in animals (Grant et al.; Mowat et al., Boogaerts, Declercq et al., 1993) and humans (Boogaerts, Lafont et al., 1996). The slow release of drug from the liposomal depot decreases the potential for systemic toxicity, and allows for administration of a greater dose. The effectiveness of liposomal bunivacaine in providing prolonged analgesia in a rat postoperative wound model has been demonstrated (Grant el al.). Formulations described to date, however, have drug-to-lipid ratios, which are too low to be clinically useful in humans.
Further issues must also be resolved before liposomal local anesthetics can be used to manage acute pain in patients. Critical requirements for a liposomal formulation include reliability and reproducibility in manufacturing and performance, and adequate shelf stability to permit long term storage. Liposomal local anesthetic compositions, which have been described in the literature, employ multilamellar vesicles (MLV) and large unilamellar vesicles (LUV). These liposomes are stored in aqueous media, whereby the component lipids are subject to degradation due to oxidation and hydrolysis. Moreover, encapsulated drug may leak from the liposome into the aqueous medium.
It is therefore desirable to provide a liposomal anesthetic formulation which has a high loading of drug, relative to total lipids and to total volume, and which has long term storage stability.